Compositions comprising 2-[(1r,6r)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate

ABSTRACT

Various aspects of the disclosure relate to 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and compositions comprising 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the United States national stage under 35U.S.C. § 371 of International Application No. PCT/US19/065197, filedDec. 9, 2019, which claims priority to U.S. patent application Ser. No.16/683,055, which granted as U.S. Pat. No. 10,864,459, and to U.S.patent application Ser. No. 16/680,365, which granted as U.S. Pat. No.10,610,805; this patent application claims priority to the precedingapplications and the following provisional patent applications: U.S.62/777,608, filed Dec. 10, 2018; U.S. 62/780,181, filed Dec. 14, 2018;U.S. 62/787,724, filed Jan. 2, 2019; U.S. 62/803,412, filed Feb. 8,2019; US 62/812,852, filed Mar. 1, 2019; US 62/818,695, filed Mar. 14,2019; U.S. 62/821,971, filed Mar. 21, 2019; U.S. 62/832,009, filed Apr.10, 2019; U.S. 62/839,569, filed Apr. 26, 2019; U.S. 62/860,218, filedJun. 11, 2019; U.S. 62/925,203, filed Oct. 23, 2019; and U.S.62/933,742, filed November 11, 2019; and the contents of eachapplication identified in this paragraph is incorporated by reference inits entirety.

BACKGROUND

The Cannabis plant generally produces cannabinoids that are carboxylicacids. These carboxylic acids display only nominal pharmacological andpsychoactive activity. The carboxylic acids can be converted intodecarboxylated cannabinoids that display robust pharmacological andpsychoactive effects, for example, by combusting Cannabis.

Decarboxylated cannabinoids are also produced industrially by heatingcannabinoid carboxylic acids under vacuum. Decarboxylated cannabinoidsare sparingly soluble in water, and attempts have been made to improvesolubility, for example, by emulsification to produce beverages suitablefor human consumption. Thermostable emulsions frequently displayunfavorable characteristics including undesirable taste. Improvedmethods of solubilizing cannabinoids are desirable to produce beveragescomprising cannabinoids.

BRIEF DESCRIPTION

Various aspects of the disclosure relate to a composition, comprising2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol(“1R,6R CBD”) at a molar ratio of 1:10 to 10,000:1.

In some embodiments, a composition is a liquid. In some embodiments, acomposition has a pH, and the pH of the composition is 7 to 13. In somespecific embodiments, the pH of the composition is 8 to 10. In some veryspecific embodiments, the pH of the composition is 8.5 to 9.5. In somespecific embodiments, the pH of the composition is 9.0 to 11.0.

In some specific embodiments, a composition comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of 1:1 to 100:1. In some specific embodiments, acomposition comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of 100:1 to 10,000:1

In some embodiments, a composition comprises water. In some specificembodiments, a composition comprises water at a concentration by weightof 50% to 99.99%. In some very specific embodiments, a compositioncomprises water at a concentration by weight of 80% to 99.99%.

In some embodiments, a composition comprises ethanol. In some specificembodiments, a composition comprises ethanol at a concentration byweight of 50 parts per million to 2%. In some specific embodiments, acomposition comprises ethanol at a concentration by weight of 1% to 20%.In some specific embodiments, a composition comprises ethanol at aconcentration by weight of 10% to 95%.

In some specific embodiments, a composition comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateat a concentration of 1 milligram per liter to 100 milligrams per liter.In some specific embodiments, a composition comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate at a concentration of 50 milligrams per liter to 5 gramsper liter. In some specific embodiments, a composition comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateat a concentration of 2 grams per liter to 200 grams per liter.

In some embodiments, a composition comprises one or more of sodium ion(Na⁺), potassium ion (K⁺), calcium ion (Ca²⁺), magnesium ion (Mg²⁺),chloride ion (Cl⁻), sulfate (SO₄ ²⁻), bicarbonate (HCO₃ ⁻), carbonate(CO₃ ²⁻), hydrogen phosphate (HPO₄ ²⁻), hydrogen pyrophosphate (HP₂O₇³⁻), hydrogen triphosphate (HP₃O₁₀ ⁴⁻), and triphosphate (P₃O₁₀ ⁵⁻).

In some embodiments, a composition comprises one or more of caffeine,thiamine, niacin, nicotinamide, riboflavin, pantothenate, sucrose,fructose, glucose, acesulfame, saccharin, stevioside, rebaudioside A,sucralose, tagatose, erythritol, maltitol, xylitol, mannitol, isomalt,and a mogroside.

In some embodiments, a composition comprises a solid phase, the solidphase comprises a salt, and the salt comprises2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.In specific embodiments, a salt comprises a cation selected from sodium,potassium, calcium, zinc, magnesium manganese, iron(II), iron(III),copper, thiamine, choline, citicoline, lysine, and arginine.

DETAILED DESCRIPTION

Various aspects of the disclosure relate to2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand compositions comprising2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.

2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate

In some embodiments, a composition comprises a salt of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.The salt can be, for example, a sodium, potassium, calcium, zinc,magnesium, manganese, iron(II), iron(III), copper, choline, citicoline,thiamine, lysine, or arginine salt.

In some embodiments, a composition comprises 1R,6R CBD.

In some embodiments, a composition comprises water, ethanol, or bothwater and ethanol.

In some embodiments, a composition comprises sodium ion at aconcentration of at least 10 parts per billion (“ppb”) by weight. Acomposition can optionally comprise sodium ion at a concentration of 10ppb to 10% by weight.

In some embodiments, a composition comprises potassium ion at aconcentration of at least 10 ppb by weight. A composition can optionallycomprise potassium ion at a concentration of 10 ppb to 10% by weight.

Exemplification

The examples disclose specific embodiments that do not limit thisdisclosure or any patent claim that matures from this disclosure.

Example 1. Determining pH stability of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolatein Water

1 gram of 1R,6R CBD was dissolved in 6.6 milliliters of 0.5 molarpotassium hydroxide (0.5 M KOH) in ethanol to produce2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.The solution was then diluted with 100 millimolar sodium carbonate (100mM Na₂CO₃) in water to a final volume of 50 milliliters and a2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate concentration of approximately 20 grams per liter. 0.5milliliters of the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolatesolution was added to each of 25 test tubes containing 9.5 millilitersof 0.1 molar carbonate/bicarbonate (CO₃ ²⁻/HCO₃ ⁻) buffer according toTable 1. Each test tube contained approximately 10 milligrams of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateat a concentration of approximately 1 gram per liter, approximately0.66% ethanol by weight, trace potassium ion, and variable sodium ion,carbonate ion, and bicarbonate ion. pH's were confirmed by multipledifferent measurements.

TABLE 1 Aqueous compositions comprising 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3- hydroxy-5-pentylphenolateat variable pH 0.1M 0.1M Sample pH Na₂CO₃* NaHCO₃ 1 9.1 0.06 mL 8.94 mL2 9.2 0.20 mL 8.80 mL 3 9.3 0.36 mL 8.64 mL 4 9.4 0.56 mL 8.44 mL 5 9.50.80 mL 8.20 mL 6 9.6 1.08 mL 7.92 mL 7 9.7 1.41 mL 7.59 mL 8 9.8 1.78mL 7.22 mL 9 9.9 2.21 mL 6.79 mL 10 10.0 2.67 mL 6.33 mL 11 10.3 4.25 mL4.75 mL 12 10.3 4.25 mL 4.75 mL 13 10.3 4.25 mL 4.75 mL 14 10.4 4.79 mL4.21 mL 15 10.4 4.79 mL 4.21 mL 16 10.4 4.79 mL 4.21 mL 17 10.5 5.32 mL3.68 mL 18 10.5 5.32 mL 3.68 mL 19 10.5 5.32 mL 3.68 mL 20 11.0 7.42 mL1.58 mL 21 11.0 7.42 mL 1.58 mL 22 11.0 7.42 mL 1.58 mL 23 11.5 8.44 mL0.56 mL 24 11.5 8.44 mL 0.56 mL 25 11.5 8.44 mL 0.56 mL

The amount of Na₂CO₃ in Table 1 does not include the ˜0.5 mL of 0.1 MNa₂CO₃ that was added with the 0.5 mL of 20 gram-per-liter solution of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.

It was expected that2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolatewould form 1R,6R CBD at pH's below a threshold pH as evidenced by anexpected color change from purple (indicative of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate)to yellow-brown (indicative of 1R,6R CBD). No color change occurred atpH's of 9.1 and above. This finding suggested that either the pK_(a) of1R,6R CBD is less than 9.1, at least in dilute aqueous solutions, orthat it may be possible to kinetically trap2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolatein an aqueous solution at a pH below the pK_(a) of 1R,6R CBD.

Example 2. Determining the approximate pK_(a) of IR, 6R CBD 0.5milliliters of the 20 gram-per-liter solution of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolatedescribed in Example 1 was diluted with 9.5 milliliters of distilledwater comprising varying concentrations of sodium bicarbonate, and colorwas monitored as shown in Table 2. pH's were confirmed by multipledifferent measurements.

TABLE 2 Samples used to determine an approximate pK_(a) for 1R,6R CBDNaHCO₃ concentration Sample pH in millimolar color 26 8.0 1000 faintpurple 27 8.3 500 light purple 28 8.6 250 purple 29 8.9 125 purple 309.2 62 purpleA color change was visually apparent at a pH of 8.0, and a subtle colorchange was visually apparent at pH of 8.3. These findings suggest thatthe pK_(a) of 1R,6R CBD was between 8.0 and 8.5 under the testconditions. This result is surprising given that previously reportedpK_(a)'s for 1R,6R CBD range from 9.13 to 9.64 and because thechemically-related molecule resorcinol has a pK_(a) of 9.15. Further,even though sample 26, which had a pH of 8.0, displayed a color changeindicative of conversion from2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateto 1R,6R CBD, no lipid phase formed, which suggests that theinterconversion between2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand 1R,6R CBD in aqueous solution can kinetically trap 1R,6R CBD in theaqueous phase and inhibit the production of a lipid phase. Thesefindings suggest that2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate,the conjugate base of 1R,6R CBD, is suitable for use in beverages forhuman consumption.

Example 3. Confirming Commercial Viability of Beverages Comprising2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate

20 milliliters of water was removed from a 1 liter bottle of ESSENTIA®OVERACHIEVING H₂O®. ESSENTIA® OVERACHIEVING H₂O® contains purifiedwater, sodium bicarbonate, dipotassium phosphate, magnesium sulfate, andcalcium chloride, and its pH was determined to be about 9.5. The 20milliliters of removed water was replaced with 20 milliliters of the 20gram-per-liter solution of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate,which is described in Example 1, and the bottle was hermetically sealedusing the screw cap top of the bottle to produce a hermetically-sealedcontainer comprising approximately 400 milligrams of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.The pH of the liquid was measured and determined to be about 10. Theliquid was purple and transparent. 5 milliliters of water was removedfrom a 500 milliliter bottle of DASANI® purified water.

DANSANI® purified water contains purified water, magnesium sulfate,potassium chloride, and sodium chloride, and its pH was determined to beabout 7.0. The 5 milliliters of removed water was replaced with 5milliliters of the 20 gram-per-liter solution of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate,which is described in Example 1, and the bottle was hermetically sealedusing the screw cap top of the bottle to produce a hermetically-sealedcontainer comprising approximately 100 milligrams of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.The pH of the liquid was measured and determined to be about 9.5. Theliquid was transparent and purple.

0.5 milliliters of water was removed from a 500 milliliter bottle ofDASANI® purified water. DANSANI® purified water contains purified water,magnesium sulfate, potassium chloride, and sodium chloride, and its pHwas determined to be about 7.0. The 0.5 milliliters of removed water wasreplaced with 0.5 milliliters of the 20 gram-per-liter solution of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate, which is described in Example 1, and the bottle washermetically sealed using the screw cap top of the bottle to producehermetically-sealed container comprising approximately 10 milligrams of2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.The pH of the liquid was measured and determined to be about 8.5. Theliquid was transparent and lacked discernable color.

The preceding experiments confirm that2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateis suitable for use in beverages.

1-21. (canceled)
 22. A composition, comprising one or both of sodium ion(“Na+”) and potassium ion (“K+”); one or more of caffeine, thiamine,niacin, nicotinamide, riboflavin, pantothenate, sucrose, fructose,glucose, acesulfame, saccharin, stevioside, rebaudioside A, sucralose,tagatose, erythritol, maltitol, xylitol, mannitol, isomalt, and amogroside;2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate;and2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol,wherein the composition comprises the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol at a molar ratio of at least 1:10 andno greater than 10,000:1.
 23. The composition of claim 22, comprisingthe2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of at least 1:1 and no greater than 100:1.
 24. Thecomposition of claim 22, comprising xylitol.
 25. The composition ofclaim 22, comprising ethanol.
 26. The composition of claim 22, water.27. The composition of claim 22, comprising water at a concentration byweight of at least 50 percent and no greater than 99.99 percent.
 28. Acomposition, comprising potassium ion (“K+”); xylitol;2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate;and 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol.29. The composition of claim 28, comprising the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of at least 1:10 and no greater than 10,000:1.
 30. Thecomposition of claim 28, comprising the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of at least 1:1 and no greater than 100:1.
 31. Thecomposition of claim 28, comprising a solid phase, wherein the solidphase comprises a salt, and the salt comprises the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the potassium ion.
 32. The composition of claim 28, comprisingethanol.
 33. The composition of claim 28, comprising water.
 34. Thecomposition of claim 28, comprising water at a concentration by weightof at least 50 percent and no greater than 99.99 percent.
 35. Acomposition, comprising sodium ion (“Na+”); xylitol;2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate;and 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol.36. The composition of claim 35, comprising the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of at least 1:10 and no greater than 10,000:1.
 37. Thecomposition of claim 35, comprising the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diolat a molar ratio of at least 1:1 and no greater than 100:1.
 38. Thecomposition of claim 35, comprising a solid phase, wherein the solidphase comprises a salt, and the salt comprises the2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolateand the sodium ion.
 39. The composition of claim 35, comprising ethanol.40. The composition of claim 35, comprising water.
 41. The compositionof claim 35, comprising water at a concentration by weight of at least50 percent and no greater than 99.99 percent.